The proposed research is aimed at further defining the molecular mechanisms of the polymerization and gelation of deoxy hemoglobin S, exploration of the cellular determinants of red cell sickling and abnormalities of the red cell membrane in sickling disorders, attempts to modify and inhibit gelation, sickling and membrane damage, and membrane damage, and studies of the intermolecular interactions of other mutant hemoglobins between each other and with hemoglobin S. Our methods will include studies of the gelation behavior of mixtures of Hb S and other alpha and beta chain mutants with substitutions at the molecular surface and with non-heme proteins; studies of gelation as a function of percent O2 desaturation; measurement of the interrelations of H ion, 2,3 DPG and CO2 on sickling and gelation; measurements of the viscoelastic properties of Hb S-containing gels; studies of the permeability of S-membranes to nonelectrolytes; studies of the associative behavior of Hb S and other hemoglobins by light scattering and osmometry; examination of the antisickling effects of hydrophobic compounds and alkylating agents; attempts to improve the deformability of irreversibly sickled cells.